“Integration dysfunction syndrome” (schizophrenia), formerly called “mind-split-disease”, is a typical psychiatric disorder characterized by hallucinations and delusions. Schizophrenia affects about 1% of the population, and 700,000 people are currently under treatment for schizophrenia in Japan. Late adolescence and early adulthood from the ages of 17 to 27 are the peak years for the onset of schizophrenia, and the disorder becomes chronic after those ages. Therefore, in 1996, patients with schizophrenia occupied 22% of all hospital beds. The peak years for males for the onset of this disorder are the ages of from 15 to 24, whereas the peak years for females for the onset of the same are the ages of from 25 to 34; thus, the onset in women is late. Furthermore, since menopause is another peak age for the onset of schizophrenia, female sex hormones are sometimes said to have an inhibitory effect on the pathological conditions associated with schizophrenia. However, the detailed reasons for this are still unknown. As described later herein, only symptomatic medication is used for the main treatment, and no decisive therapeutic method has yet to be established.
The involvement of a genetic factor in the onset of schizophrenia is suggested by the fact that the simultaneous onset of schizophrenia in identical twins is 35 to 58%, which is higher than that of fraternal twins, i.e., 13 to 27%. The heritability is estimated to be about 80%. Even compared with the heritability of hypertension, which is 30%, and the heritability of obesity, which is 40 to 70%, the influence of hereditary factors on schizophrenia is great. For this reason, many candidate genes have been studied since the 1990s, and the number of genes studied so far has reached the triple digits. Further, a large-scale linkage study has also been performed. Although several candidate genes have been identified by positional approaches, the pathological conditions are still inexplicable in terms of biochemistry etc. Moreover, the results of the candidate gene analyses of various researchers are inconsistent. Therefore, schizophrenia is not considered to be a so-called “hereditary disease” (monogenic disease), but rather a multifactorial genetic disease that is developed by a combination of a plurality of genes having low pathogenic effects, and environmental factors.
The main symptoms of schizophrenia are positive symptoms prominently observed during the acute phase (e.g., hallucinations, delusions, and incoherence), and negative symptoms that become prominent during the chronic phase (e.g., apathy, lack of emotion and motivation, and social withdrawal).
Diagnosis of schizophrenia is currently made based on interviews with the patient in consideration of the patient's remarks and facial expressions, sometimes with additional information from the family, according to one of the following criteria: the “International Classification of Diseases, Tenth Revision” (ICD-10) of the World Health Organization (WHO) (see FIG. 1), or the “Diagnostic and Statistical Manual, Fourth Edition” (DSM-IV) of the American Psychiatric Association (APA) (see FIG. 2). Accordingly, a final diagnosis inevitably depends on the doctor's personal opinion, based on his experience. Thus, diagnoses are not always sufficiently accurate. Therefore, the chromosomal mapping of the gene that causes schizophrenia and the identification thereof, and research using biological samples such as patient's blood or urine have been actively carried out. As a result, several biological markers that can be used for the diagnosis of schizophrenia have been reported (see Patent Documents 1 to 7). However, no decisive method has yet to be established.
The main treatment of schizophrenia is the administration of an antipsychotic (see FIG. 3). The administration must be continued almost throughout a person's entire life. The pharmacological effects of antipsychotics on hallucinations and delusions are based on dopamine receptor blocking activity. However, since the inhibition of dopamine neurons causes Parkinsonian symptoms as side effects, an anti-Parkinson's agent is generally used with the antipsychotic. In recent years, in place of conventional antipsychotics, which are effective for positive symptoms of schizophrenia but substantially ineffective for negative symptoms thereof, atypical antipsychotics that are also effective for the negative symptoms have been developed and used. Compared to conventional antipsychotics, such atypical antipsychotics have weak blocking effects on dopamine receptors, and are thus advantageous in terms of decreased side effects such as Parkinson's symptoms.
Examples of therapeutic methods other than administration of an antipsychotic include electroconvulsive therapy (ECT), which is a therapeutic method in which a general convulsion is induced by applying an alternating current of 100V for 5 seconds; and psychiatric rehabilitation, in which social skills training (SST) and occupational therapies such as farming, woodworking, handicrafts, and recreation are carried out. ECT, mentioned above as the first example, is used when immediate improvement of the condition is required, for example, in the case of immediate suicide risk, malnutrition, or catatonia, or when patients are resistant to pharmaceutical treatment. Psychiatric rehabilitation, mentioned as the second example, is used to acquire life skills and thus reduce stress in social life, thereby preventing recurrences.
However, these methods are all symptomatic treatments. Although the data is old, the results of a 15-year follow-up study of schizophrenia conducted using, as subjects, chronic intractable patients for whom drug treatment was ineffective are as follows: 6% recovered; 8% were good; 23% were moderate; 23% were marginal; and 41% continued to be incapacitated (Non-patent Document 1).
Advanced Glycation End products (hereinafter sometimes referred to as “AGEs”) are substances formed in the body by a non-enzymatic reaction (Maillard reaction) between a protein (an amino group) and a carbonyl compound produced from sugar, lipid, etc. under conditions of hyperglycemia or oxidative stress (the term “carbonyl-modified protein that is a protein modified with the carbonyl compound” as used herein includes the AGEs). AGEs are a heterogeneous group of many substances, including pentosidine. Pentosidine, which is one type of AGE structure, is a fluorescent substance that was isolated from human dura mater collagen by Sell et al. in 1989. In recent years, the results of analysis using antibodies against AGEs (anti-AGEs antibodies) have revealed that AGEs levels increase in tissues and blood in various pathological conditions. For example, in diabetes, due to hyperglycemia, an increase in the levels of sugar-derived carbonyl compounds, which are precursors of AGEs, and carbonyl-modified proteins (AGEs) is observed. Due to the decreased excretion of carbonyl compounds and increased oxidative stress in renal failure, and the increased oxidative stress in inflammatory diseases, the production of carbonyl compounds is promoted, and thus an increase in the level of carbonyl-modified proteins (AGEs) is observed. It has also been reported that AGE levels increase in patients who are deficient in glyoxalase, which is an enzyme for removing carbonyl compounds. Therefore, blood AGE levels are actually used in clinical tests as an indicator of vascular complications resulting from diabetes and renal failure. Examples of methods of determining AGE levels include an ELISA method of measuring the amount of pentosidine, which is one of the AGE structures, using an anti-pentosidine antibody; and a method of measuring the amount of pentosidine in skin using an AGE Reader.    Patent Document 1: Japanese Unexamined Patent Publication No. 2001-245661    Patent Document 2: Japanese Unexamined Patent Publication No. 2003-38198    Patent Document 3: Japanese Unexamined Patent Publication No. 2003-212795    Patent Document 4: WO2004/005935 pamphlet    Patent Document 5: Japanese Unexamined Patent Publication No. 2004-251865    Patent Document 6: Japanese Unexamined Patent Publication No. 2005-55227    Patent Document 7: Japanese Unexamined Patent Publication No. 2005-278490    Non-patent Document 1: McGlashan, Schizophr Bull, 1988